Ergothioneine was discovered at the beginning of the 20th century in an ergot fungus contaminant of rye. Tenret, 1909, Comp. Rend. Acad. Sci. 149:222-224. The compound ergothioneine has been shown to protect cells from reactive oxidative species in bacteria, fungi, plants, and animals, including humans. Paul & Snyder, 2010, Cell Death Differ. 17:1134-1140; Emani et al., 2013, Antimicrob. Agents Chemother. 57:3202-3207. However, only certain bacteria and certain fungi have been shown to produce the compound themselves. Fahey, 2001, Annu. Rev. Microbiol. 55:333-356. Plants acquire ergothioneine from microbes in the soil. Audley & Tan, 1968, Phytochemistry 7:1999-2000. Animals, including humans, absorb ergothioneine from their diet. Humans have a specific transporter, ETT, for the uptake of ergothioneine. Gründemann et al., 22005012, Proc. Natl. Acad. Sci. USA 102:5256-5261. Cells that express ETT accumulate and retain ergothioneine at high levels. Id. The compound has a long biological half-life in the cell. Wolf et al., 1961, Biochem. Biophys. Acta 54:287-293. It is believed that ergothioneine provides antioxidant cytoprotection in such cells. Paul & Snyder, supra.
To date, ergothioneine has been proposed and used in several human and animal products. These include use as a skin toner additive (U.S. Pat. No. 7,122,211), as a photoprotective agent for human skin (U.S. Pat. No. 7,022,317), for the amelioration of liver disease (U.S. Pat. No. 6,555,141), for preventing diseases associated with oxidative damage to mitochondria (U.S. Pat. No. 6,479,533; U.S. Pat. No. 6,103,746), for repair of skin connective tissue damage (U.S. Pat. No. 6,451,771), and for other pharmaceutical antioxidant uses (U.S. Pat. No. 6,326,034; U.S. Pat. No. 6,056,965).
However, synthesis of ergothioneine has proved difficult and expensive. Commercial sources of ergothioneine can cost tens of thousands of dollars per gram. Prior syntheses of ergothioneine have involved many steps, challenging yields, and potentially toxic reagents. See, e.g., U.S. Pat. Nos. 5,438,151, 7,767,826, and 8,399,500. Improved methods for preparing ergothioneine on an industrial scale are needed.